Paired Acute Inhalation Test Reveals That Acetaldehyde Toxicity Is Higher in Aldehyde Dehydrogenase 2 Knockout Mice Than in Wild-Type Mice

Abstract

-Aldehyde dehydrogenase 2 (ALDH2) is an important enzyme that oxidizes acetaldehyde.Approximately 45% of Chinese and Japanese individuals have the inactive ALDH2 genotypes (ALDH2*2/ *2 and ALDH2*1/*2); acute inhalation toxicity of acetaldehyde has not been evaluated in these populations. We compared the toxicity between wild-type (Aldh2+/+) and Aldh2-inactive transgenic (Aldh2−/−) mice by using the paired acute inhalation test modified from the acute toxic class method (OECD TG433). Blood acetaldehyde level was measured 4 hr after the inhalation. A pair of Aldh2+/+ and Aldh2−/− mice was put into a chamber and was exposed to 5000 ppm of acetaldehyde. At the start of the inhalation, the mice exhibited hypoactivity and closing of the eyes. Subsequently, symptoms such as crouching, bradypnea, and piloerection were observed. Flushing was observed only in the Aldh2+/+ mice. Symptoms such as tears, straggling gait, prone position, pale skin, abnormal deep respiration, dyspnea, and one case of death were observed only in the Aldh2−/− mice. The symptoms did not change 1 hr after inhalation in the Aldh2+/+ mice. In contrast, in the Aldh2−/− mice, the symptoms became more severe until the end of the inhalation. The blood acetaldehyde level in the Aldh2−/− mice was approximately twice that in the Aldh2+/+ mice 4 hr after inhalation. The Aldh2−/− mice evidently showed more severe toxicity as compared with the Aldh2+/+ mice due to acute inhalation of acetaldehyde at a concentration of 5000 ppm. Acetaldehyde toxicity in Aldh2+/+ and Aldh2−/− mice was estimated and classified one class different. Based on this study, acetaldehyde inhalations were inferred to pose a higher risk to ALDH2-inactive human individuals.

Characteristics of aldehyde dehydrogenase 2 (Aldh2) knockout mice

“…Exposure to acetaldehyde is not only due to ethanol consumption but also due to the use of acetylaldehyde in industrial and household materials (Isse et al 2005b). Oyama et al (2007a) reported inhalation toxicity of acetaldehyde in Aldh2 knockout mice.…”

“…Acetaldehyde is widely produced as an intermediary product of alcohol, acetic acid, certain esters, and a number of other chemicals in ethylene and alcohol fermentation plants; it is also present in tobacco smoke (IPCS 1995;Isse et al 2005b). Acetaldehyde is rapidly metabolized to acetic acid by aldehyde dehydrogenase (ALDH).…”

“…More than 95% of ethanol-derived acetaldehyde is oxidized by the liver mitochondrial ALDH2 (Eriksson 1977;Isse et al 2005b). ALDH2-deficient individuals exhibit a so-called 'flushing response' , which includes facial flushing, palpitation, and drowsiness, as well as other unpleasant symptoms due to delay of acetaldehyde dehydrogenation (Muramatsu et al 1989;Ogawa et al 2007).…”

A Pirot Study on Subacute Ethanol Treatment of Aldh2 Ko Mice

“…However, there has been little evidence as to whether the toxic effect is different according to the activity of the Aldh2 enzyme (Isse et al, 2005a(Isse et al, , 2005b(Isse et al, , 2005cOyama et al, 2005), which is a major enzyme in ethanol metabolism. In this study, the weights of the mice were decreased to 85% and 74% of the control Aldh2 +/+ and Aldh2 −/− group, respectively, when ethanol was administered.…”

“…Aldh2 −/− mice were maintained with a C57BL/6 strain and backcrossed with C57BL/6 strain for more than 10 generations for the experiments at the animal center of University of Occupational and Environmental Hearth (UOEH) (The Jackson laboratory mouse genome informatics # 99600 ) (Isse et al, 2005b). These mice were housed in specific pathogen-free units of the Division of Animal Care at the University of Occupational and Environmental Health.…”